The basal level of intracellular calcium gates the activation of phosphoinositide 3-kinase-Akt signaling by brain-derived neurotrophic factor in cortical neurons
Article first published online: 11 MAY 2008
© 2008 The Authors. Journal Compilation © 2008 International Society for Neurochemistry
Journal of Neurochemistry
Volume 106, Issue 3, pages 1259–1274, August 2008
How to Cite
Zheng, F., Soellner, D., Nunez, J. and Wang, H. (2008), The basal level of intracellular calcium gates the activation of phosphoinositide 3-kinase-Akt signaling by brain-derived neurotrophic factor in cortical neurons. Journal of Neurochemistry, 106: 1259–1274. doi: 10.1111/j.1471-4159.2008.05478.x
- Issue published online: 15 JUL 2008
- Article first published online: 11 MAY 2008
- Received January 10, 2008; revised manuscript received May 2, 2008; accepted May 2, 2008.
- brain-derived neurotrophic factor;
- mitogen-activated protein kinase;
- phosphoinositide 3-kinase;
- synaptic plasticity
Brain-derived neurotrophic factor (BDNF) mediates survival and neuroplasticity through the activation of phosphoinositide 3-kinase-Akt pathway. Although previous studies suggested the roles of mitogen-activated protein kinase, phospholipase C-γ-mediated intracellular calcium ([Ca2+]i) increase, and extracellular calcium influx in regulating Akt activation, the cellular mechanisms are largely unknown. We demonstrated that sub-nanomolar BDNF significantly induced Akt activation in developing cortical neurons. The TrkB-dependent Akt phosphorylation at S473 and T308 required only phosphoinositide 3-kinase, but not phospholipase C and mitogen-activated protein kinase activity. Blocking NMDA receptors, L-type voltage-gated calcium channels, and chelating extracellular calcium by EGTA failed to block BDNF-induced Akt phosphorylation. In contrast, chelating [Ca2+]i by 1,2-bis(o-aminophenoxy)ethane-N,N,N ′,N ′-tetraacetic acid-acetoxymethyl ester (BAPTA-AM) abolished Akt phosphorylation. Interestingly, sub-nanomolar BDNF did not stimulate [Ca2+]i increase under our culture conditions. Together with that NMDA- and membrane depolarization-induced [Ca2+]i increase did not activate Akt, we conclude that the basal level of [Ca2+]i gates BDNF function. Furthermore, inhibiting calmodulin by W13 suppressed Akt phosphorylation. On the other hand, inhibition of protein phosphatase 1 by okadaic acid and tautomycin rescued Akt phosphorylation in BAPTA-AM and W13-treated neurons. We further demonstrated that the phosphorylation of phosphoinositide-dependent kinase-1 did not correlate with Akt phosphorylation at T308. Our results suggested novel roles of basal [Ca2+]i, rather than activity-induced calcium elevation, in BDNF-Akt signaling.